A wide range of subcutaneous drug delivery devices are known in which a drug is stored in an expandable-contractible reservoir. In such devices, the drug is delivered from the reservoir by forcing the reservoir to contract. (The term xe2x80x9csubcutaneousxe2x80x9d as used herein includes subcutaneous, intradermal and intravenous.)
Such devices can be filled in the factory or can be filled by the pharmacist, physician or patient immediately prior to use. In the former case it may be difficult to provide the required drug stability in the device since the drug will be stored in the reservoir for a shelf life of from several months to a number of years. In the latter case, it is difficult to ensure that the drug has completely filled the reservoir, i.e. that the reservoir and fluid path do not contain any air bubbles. In general, this requires priming the device by filling it in a certain orientation which ensures that the air bubbles are pushed ahead of the drug, such as with the filling inlet at the bottom and the delivery outlet at the top (to allow the bubbles of air to rise during filling).
A further problem associated with subcutaneous drug delivery devices is that in many cases gas generation is used to compress the reservoir. While it may be possible to ensure a constant or a controllably varying rate of gas generation (for example by passing a constant current through an electrolytic cell), this does not ensure a constant rate of drug delivery.
The amount of compression of the reservoir (and thus the rate of delivery of drug) depends on the amount by which the volume of the gas generation chamber expands. The behavior of an ideal gas is governed by the equation PV=nRT, in which the volume of gas, V, is proportional to the number of moles of gas, n, and the temperature, T, and inversely proportional to the pressure, P.
An electrolytic cell working at constant current will generate a constant number of moles of gas per unit time. However, changes in the temperature of the gas and in the atmospheric pressure exerted on the gas will cause the volume to vary. Even if the temperature of the device remains constant, the fact that atmospheric pressure drops by approximately 3% for every increase in altitude of 300 m means that the delivery rate will vary substantially between a location at sea level and a higher altitude location (for example, Denver, Colo. is approximately 1 mile or 1.6 kilometers above sea level, so atmospheric pressure will be approximately 17% lower on average than at sea level). Similarly, normal changes in atmospheric pressure due to the weather cause the delivery rate of this type of device to vary.
For devices which employ a needle to penetrate the skin there is a danger that after use the device may accidentally infect the patient or others if not properly disposed of. WO 95/13838 discloses an intradermal device of this type having a displaceable cover which is moved between a first position in which the needle is retracted before use and a second position in which the needle is exposed during use. Removal of the device from the skin causes the cover to return to the first position in which the needle is again retracted before disposal. However, this device does not include a locking mechanism in the assembly for locking the device prior to use to minimize accidental contact with the needle and/or accidental actuation of the device that may occur during shipping and/or storage.
When filling a drug delivery device, the conventional method is to use a syringe, which carries the risk of accidental injury. The present invention has as a further aim the improvement of safety when syringes are used. The present invention also aims to decrease the possibilities that the needle could become exposed by accident before or after use, for example, by a child playing with the device if not properly disposed of. Clearly given the risks associated with infectious diseases, particularly those carried by blood, any possibility of accidental infection must be minimized to the utmost and preferably eliminated entirely.
Our International Application No. PCT/IE 96/00059 discloses a medicament delivery device having a filling mechanism integral within the housing which receives a cylindrical cartridge (or xe2x80x9cvialxe2x80x9d) sealed by a sliding stopper. When the cartridge is pushed into the filling mechanism, a hollow needle in the filling mechanism penetrates the stopper and establishes communication between the interior of the cartridge and the device""s internal reservoir. Continued movement of the cartridge into the filling mechanism causes the stopper to slide into the cartridge and act as a piston to pump the medicament from the cartridge into the reservoir. While this mechanism overcomes some of the disadvantages of using a syringe, it also makes the device bulkier.
Thus, there is a need to provide a subcutaneous drug delivery device having an improved filling mechanism which facilitates filling the device in an orientation-independent manner.
There is a further need to provide a filling system that is less bulky.
There is still a further need to provide a filling system that maintains the needles within the system in a recessed fashion so as to minimize the risk of injury associated with needles.
There is yet a further need to provide a device which operates at a substantially constant delivery rate independently of the ambient atmospheric pressure.
There is a further need to provide a drug delivery device in which the needle is retracted from the housing surface before and after use so as to minimize injury due to accidental contact with the needle.
There is yet a further need to provide a device having improved adhesion to the skin, i.e. for which there is less likelihood that the device will become detached during use.
The present invention overcomes these and other disadvantages associated with prior art drug delivery devices and filling systems. Stated generally, the present invention provides for a drug delivery device having a housing that has an internal reservoir and an expandable chamber disposed relative to the reservoir. The device also has a drug delivery needle extending from the housing for penetration of the skin of a subject. The needle has an outlet for drug delivery. The drug delivery device of the present invention further includes a fluid path defined between the delivery needle outlet and the reservoir and means for providing a gas at a controllable rate into the expandable chamber. The device also includes a flow regulating chamber, in communication with the fluid path, which is capable of volumetric changes in response to temperature and/or pressure changes.
By calibrating the degree of increase or decrease in flow resistance, it is possible to compensate for differences occurring in the rate of delivery which arise because of pressure- or temperature-induced differences in the volume of a given mass of gas in the expandable chamber. Thus, if the ambient atmospheric pressure drops, the gas in the expandable chamber will tend to expand and thereby force more drug from the reservoir. This will however be counteracted by the flow regulating chamber which will increase flow resistance along the fluid path and thereby counteract the increased flow rate arising from the effect of the tendency for the expandable chamber to expand.
Preferably, the expandable chamber causes contraction of the reservoir in use. Further, preferably, the flow regulating chamber alters the drug delivery rate by varying the flow resistance between the reservoir and the outlet. Preferably, the flow regulating chamber is associated with a blocking member which upon expansion of the flow regulating chamber moves within the fluid path so as to restrict the flow of drug.
Further, preferably, the blocking member comprises a formation provided on a displaceable member which at least partially bounds the flow regulating chamber, the formation being disposed adjacent to an inlet of a conduit forming part of the fluid path, such that restriction of the fluid path occurs when the blocking member is moved into the inlet of the conduit. By having a suitably shaped and sized formation relative to the inlet, it is possible to precisely vary the flow resistance of the conduit, and thereby precisely control the delivery rate notwithstanding changes in ambient temperature and/or pressure.
Suitably, the shape of the blocking member is adapted to cut off the fluid path completely with a predetermined degree of expansion of the flow regulating chamber. Alternatively, the formation can be shaped such that the fluid path is never entirely cut off.
In preferred embodiments of the invention, a displaceable cover is connected to the housing such that displacement of the housing relative to the cover when the cover has been applied to the skin of a subject causes the delivery needle to penetrate the skin of the subject. Such a displaceable cover is suitable for concealing the needle before and after application to the skin of a subject, which prevents injury and reduces the possibility of contamination of the needle.
In another aspect of the invention the expandable chamber is provided with a release valve operatively connected to the displaceable cover such that the movement of the housing relative to the cover controls the closing of the valve and thereby the sealing of the expandable chamber. This feature is not dependent on the existence of the flow regulating chamber.
The valve enables the device to be supplied with the displaceable member positioned such that the volume of the (empty) reservoir is minimized and that of the expandable chamber maximized. Thus, the reservoir can be of substantially zero volume initially, with no entrapped air volume. The device can then be primed or loaded by filling the reservoir, for example using a syringe- or cartridge-based filling mechanism. As the reservoir is filled, the displaceable member moves to expand the reservoir and thereby contract the expandable chamber. The valve allows the air or other gas in the expandable chamber to be exhausted into the atmosphere.
The device can then be applied to the skin of the user. When the device is applied the housing moves relative to the cover which is applied to the skin, not only does the needle penetrate the skin, but also (because the valve is operatively connected to the cover) the valve is closed to seal the expandable chamber. If the valve remained open then gas supplied into the expandable chamber would be free to escape and delivery would not be effected. While it would be possible for the user to close the valve manually, this would clearly leave open the possibility of error. Instead, by connecting the valve operatively to the cover, it is possible to ensure that the valve is always closed when the device is applied to the skin.
Preferably the valve comprises two components one of which is connected to the cover and the other of which is connected to the expandable chamber, such that relative movement of the housing towards the cover causes the valve to close.
The invention includes a displaceable cover that is displaceable relative to the housing between a first position in which the needle is concealed from the exterior of the device, and a second position in which the delivery needle protrudes from the device for penetration of the skin. A further aspect of the present invention comprises means for locking the device in the first position after a single reciprocation of the device from the first position to the second position and back to the first position.
The displaceable cover is an advantageous feature since it solves a problem unaddressed by prior art devices. Our prior art device has a locking mechanism to lock the housing in place after use and keep the needle concealed. However, there is no mechanism to prevent premature activation prior to intended use that may cause the needle to protrude accidentally thereby giving rise to injury. According to the present invention, however, the locking means engages automatically when the cover and housing are reciprocated relative to one another, i.e. the housing and cover are moved relative to one another to cause the needle to protrude when the device is applied to the skin. This relative movement is reversed when the device is removed thereby concealing the needle but also engaging the locking means to prevent the needle from being exposed again by accident.
In a preferred embodiment, the locking means comprises a mechanical latch which is brought into operation by the reciprocation. Further, it is preferred that the latch comprises a pair of elements mounted on the cover and the housing respectively. It is preferred that the elements be shaped such that they can have two relative configurations when the cover is in the first position relative to the housing. It is preferred the elements have a first movable configuration in which the elements are mutually movable, and a second locked configuration in which the elements are prevented from mutual movement. It is also preferred that the reciprocation of the cover and the housing causes the elements to pass from the first movable configuration, through an intermediate configuration when the cover is in the second position relative to the housing, and then to the second locked configuration, thereby preventing any further movement of the cover relative to the housing.
In preferred embodiments illustrated further below, one of the elements is provided with a recess which is adapted to receive a projection on the other of the elements, the recess and the projection being spaced apart from one another in the movable configuration, and being in engagement with one another in the locked configuration.
These embodiments are preferred because while they are mechanically simple and easy to make, their very simplicity provides fewer opportunities for malfunction.
In a preferred embodiment of the present invention, movement of the cover relative to the housing is initially prevented by a removable locking member. This feature helps to prevent accidental injury occurring because the needle is only exposed when the housing is moved relative to the cover, i.e. only after the user has specifically removed the removable locking member. The presence of the removable locking member also prevents the means for providing a gas from being actuated. This prevents the device from being exhausted by accidental switching on at an incorrect time. In a preferred embodiment of the present invention, the removable locking member comprises a laminar member inserted between the cover and the housing.
In a further aspect of the invention, the surface of the housing from which the needle extends or the surface of the displaceable cover, if present, is of a concave cross-section. When the device has been applied to the skin of a subject, removal of the device is resisted because the cover conforms more closely to the skin. In prior art devices, it has been found that retention on the skin of the user is problematic because of adhesive failure, for example. Using a concave surface causes the device to be retained more effectively by adhesive means.
With prior art devices the lower surface tends to be peeled away from the skin more easily as the edges of the device can be detached relatively easily. Where a concave lower surface is used the edges tend to remain in contact with the skin and removing the device is thus more difficult. In effect a shear force is required rather than a simple peeling, and this assists in preventing accidental removal. This feature is not dependent on the existence of the other aspects of the invention.
In a modified device according to the invention, the needle extends from the lower surface of the housing is replaced by a tube extending from the housing. The tube is adapted for carrying a drug delivery needle. Such a device is preferred for intravenous delivery of a drug as the needle carried on the end of the tube can be accurately located in a suitable vein. The needle may be integral with the tube or supplied separately.
In a further preferred feature of the present invention, the drug reservoir is separated from the expandable chamber by a diaphragm. The diaphragm exhibits bistable behavior such that in one stable state the reservoir is full and in the other stable state the reservoir is empty. The diaphragm is shaped to minimize the energy required in the transition between the stable states. In a preferred embodiment of the present invention, the diaphragm is in the form of a body having a peripheral lip connected to a substantially flat central section by a flexible annular section. The flexible annular section assumes a substantially frusta-conical cross-section in one of the states and assuming an arcuate curved cross-section in the other state.
Preferably, the means for providing a gas comprises an electrical circuit in which any transistors are bipolar transistors having a gain of not less than 500, such that the circuit can be irradiated by ionizing radiation without destroying the circuit.
This type of transistor has been found to be advantageous as it enables the device to be sterilized using gamma radiation with the electronic components intact. While a certain loss of performance results from the irradiation, the high gain transistor still has an adequate gain after irradiation to operate reliably. It is preferred that the current gain of the or each transistor is not less than 750. For example, a transistor having a rated current gain of 800 has been found to give an excellent performance after irradiation, despite the fact that irradiation lowers the current gain characteristics of the transistor by a factor of ten or more. The initial high gain compensates for the subsequent reduction arising from irradiation. The fact that the effects of irradiation can be predicted means that the performance after irradiation is reliable.
It is also preferred that the circuit further include a reference component across which a fixed potential drop is measurable. The reference component is essentially unchanged by the ionizing radiation. If a reference voltage is used which is not affected by the irradiation process, then the operation of the other components in the circuit may be determined by this reference voltage. For example, while the current gain of a group of transistors may vary individually when a batch is irradiated, each such transistor can be used to make an identically functioning amplifier if the output current of the amplifier is matched against a given reference component.
Light emitting diodes (LEDs) have been found to be affected less than other standard components when irradiated by gamma radiation. Thus, the reference component of the preferred embodiment comprises a light-emitting diode. Gallium arsenide (GaAs) LEDs are virtually unaffected by gamma rays. Thus, it is preferred that the light emitting diode employs gallium arsenide as a semiconductor.
In a further aspect, the present invention provides for a subcutaneous drug delivery kit including a drug delivery device as described above. The device is provided with a filling mechanism associated with the reservoir. The filling mechanism includes means for receiving a filling adapter. The filling adapter includes a body which is adapted to accommodate a drug cartridge. The body has means for engaging the adapter-receiving means of the drug delivery device at one end thereof, means for receiving a cartridge at the other end thereof, and transfer means for transferring a liquid from a cartridge to the filling mechanism of the device as the cartridge is emptied. The adapter-receiving means and the corresponding engaging means provided on the adapter together constitute a releasable locking mechanism which holds the adapter in place on the device once engaged. The locking mechanism is disengaged by the cartridge when the cartridge is emptied within the adapter.
The kit according to the invention is advantageous because it eliminates the need for a bulky filling mechanism which accommodates the cartridge within the device, and instead employs an adapter which is releasable from the device so as to enable the filled device to be less bulky than prior art cartridge-based devices.
Furthermore, the locking mechanism employed is only disengaged when the cartridge has been completely emptied, i.e., the rubber stopper within the cartridge is pushed to the bottom. If the cartridge used is of a type which will empty when the stopper is pushed to the bottom, this feature ensures accurate loading of the reservoir, i.e. it is not possible to easily remove the device before the reservoir is filled with the correct dose of medicament.
Suitably, the transfer means comprises a hollow double-ended needle, one end of which is associated with the engaging means such that it communicates with the filling mechanism when the adapter is engaged with the device, and the other end of which is associated with the cartridge receiving means such that it communicates with the interior of a cartridge having a penetrable stopper when such a cartridge is received by the adapter.
Such a hollow double ended needle can be replaced by a pair of needles which are connected by a conduit, such as a moulded conduit running through the body of the adapter and having a needle mounted at either end such that it is functionally equivalent to a double ended needle. Preferably, both ends of the needle are disposed within the body of the adapter such that they are recessed from the exterior of the body when the adapter is disengaged from the device. This arrangement is preferable for safety reasons, as it allows the adapter to be disposed of without fear of accidental injury occurring from casual handling of the adapter.
In a preferred embodiment, the releasable locking mechanism comprises a pair of locking members provided on the adapter receiving means and the corresponding engaging means, respectively. One of the locking members is movable between a locking position and a disengaging position. The movable locking member is disposed relative to the body such that, in use, when a cartridge is emptied within the body, the movable locking member is moved from the locking position to the disengaging position under the action of the cartridge.
Where a substantially cylindrical cartridge is employed, the body can receive the cartridge within a passage having a diameter sufficient to completely accommodate the cartridge. However, the end of the passage is of slightly narrower diameter on account of a projection provided on the movable locking member. Thus, when the cartridge completely emptied by pushing the stopper to the bottom, it contacts the movable locking member and pushes it out of the way, thereby disengaging the locking mechanism.
Suitably, the movable locking member is resiliently biased towards the locking position. Preferably, the movable locking member is a latch which automatically locks the adapter and device to one another when engaged together. It is preferred that the cartridge is emptied by moving the penetrable stopper against the adapter
The present invention further provides a subcutaneous drug delivery kit including a device according to any preceding claim further comprising a filling mechanism associated with the reservoir, the filling mechanism comprising means for receiving a filling adapter as defined herein and a filling adapter. The filling adapter has a body adapted to receive a syringe. The body has means for engagement with the adapter-receiving means of the device at one end thereof, syringe-receiving means at the other end thereof and transfer means for transferring a liquid from the syringe to the filling mechanism of the device as the syringe is emptied. The transfer means includes a conduit associated with the syringe receiving means, the conduit leads to a needle which is associated with the engagement means and is disposed within the body of the filling adapter.
It is preferred that the needle disposed within the body of the filling adapter is recessed from the exterior of the body when the adapter is disengaged from the device. It is also preferred that the adapter receive the syringe without a needle. Since the needle on the adapter is recessed from the exterior of the adapter body and the syringe has no needle when filling, a conventional syringe (minus needle) can be used to fill the device without any risk of accidental injury.
A further aspect of the present invention provides a method of filling a drug delivery device. The method includes providing a drug delivery device having a drug reservoir. The reservoir is associated with a filling mechanism having filling adapter receiving means. The method further includes providing a filling adapter having a first end for engagement with the adapter receiving means, and a second end for receiving a syringe and causing the filling adapter receiving means to receive the filling adapter. The method further includes causing the second end of the filling adapter to receive a syringe having liquid stored therein and a needle, and providing a conduit for communication between the liquid stored within the syringe and the first end of the filling adapter. The method of filling further includes emptying the syringe and concurrently transferring the liquid from the syringe to the device via the conduit. In yet further aspects, the invention provides a filling adapter as defined above and a diaphragm as defined above.
In a preferred embodiment of the present invention, the electrical circuit used to provide gas to the expandable chamber includes a high voltage supply, such as, for example, between one and three batteries and current stabilizing elements, such as, for example, two resistors connected in series. The electrical circuit of this preferred embodiment simplifies the electrical circuit and stabilizes the current supplied to the electrolytic cell without using components such as transistors which are sensitive to gamma radiation used for sterilization.
Another aspect of a preferred embodiment of the drug delivery system of the present invention includes an occlusion prevention mechanism. Further, it is not desirable that the delivery rate of the drug delivery device be altitude dependent. An element, such as, for example, a valve in the drug delivery device, creates a constant high, back pressure within the gas chamber, minimizing or preferably preventing the formation of boli of drugs.
In a preferred embodiment of the present invention, an optical window, such as, for example, a ring like structure, provides a more accurate assessment of the quantity of drug delivered or alternatively, the quantity of drug remaining in the drug reservoir. The embodiment makes use of the principle of light reflected from the elastomeric membrane or diaphragm containing the drug. When the drug reservoir is approximately full, the optical window appears black as the elastomeric membrane is extended away from the housing as the drug fills it. However, when the drug reservoir is approximately empty, the optical window appears blue in color, for example, as the elastomeric membrane is proximate to the housing as drug delivery is close to completion.
Further, in a preferred embodiment, the subcutaneous drug delivery device includes a pressure sensitive mechanism for preventing a rapid injection of a drug to a user. For example, the pressure sensitive mechanism can include a switch that forms a part of the electrical circuit which controls the power supply to a gas generating portion of the drug delivery device. The switch can include different preferred components to complete the circuit, such as one including a conductive membrane and a conductive lever, or alternatively, electrodes and a droplet of mercury. The electrical circuit is completed as long as the pressure in the gas generating portion is less than the pressure within a chamber.
In another preferred embodiment, the drug delivery system in accordance with the present invention includes a visual indicator to indicate proper application and operation to a user. The indicator can be, for example, a color marking system. The color marking system can be used to indicate to a user components of the system which should be removed from the system prior to use.
Another preferred embodiment of the drug delivery system of the present invention includes an insert, for example, a foam insert that receives the internal components of the device and accommodates design tolerances. The insert maintains an accurate internal volume so that upon assembly, the volume of the internal housing, and thus the drug reservoir, is within an accurate range.
In a preferred embodiment, the drug delivery system of the present invention includes an activation mechanism, such as, for example, an activation lever to initiate gas generation in the expandable chamber which in turn controls the delivery of the drug from the device. The activation mechanism also includes a puncturing device and an electrical contact. In operation, upon depression, the puncturing device punctures the foil cover of the electrolytic cell, thereby allowing the chemical ingredients to release gas for expanding the expandable chamber. As a result, the proximate drug reservoir is compressed and drug delivery is initiated.
Another preferred embodiment of the drug delivery system relates to controlling the rate of delivery which is controlled by several parameters. The parameters include, but are not limited to, circuit current, residual air volume, material permeability, material properties of plastic material in device, and membrane seal. For example, the permeability of the drug delivery system components, such as the permeability of the materials used in the base affects the delivery rate of the drugs delivered. thus, materials such as, for example, PET that minimizes or preferably prevents the permeation of the gases generated in the device, for example, hydrogen is used. By minimizing the permeability of the gases of the expandable chamber, a constant delivery rate can be maintained. As the diffusion rate of the gases controls the delivery rate of the drug, material changes can control the delivery rate of drugs.
Another aspect of the present invention includes packaging of the drug delivery system to insulate the system from storage and use in different altitudes. In particular, the electrolyte in the electrolytic cell used to generate gas in the expandable chamber is affected by environmental conditions. Further, the performance of the barometric pressure valve can be affected by the environmental conditions as it relies on a reference pressure of a fixed amount of the air. At high altitudes, air from the reference cell can diffuse out of the device due to expansion of the air. In a preferred embodiment, by hermetically packaging the device, the barometric pressure valve has only one position, that is, it is a stationary valve as the pressure inside the device is constant.
Thus, it is an object of the present invention to provide a subcutaneous drug delivery device having an improved filling mechanism which facilitates filling the device in an orientation-independent manner.
It is a further object of the present invention to provide a filling system that is less bulky.
It is still a further object of the present invention to provide a filling system that maintains the needles within the system in a recessed fashion so as to minimize the risk of injury associated with needles.
It is yet a further object of the present invention to provide a device which operates at a substantially constant delivery rate independently of the ambient atmospheric pressure.
It is even yet a further object of the present invention to provide a drug delivery device in which the needle is retracted from the housing surface before and after use so as to minimize injury due to accidental contact with the needle.
It is yet a further object of the present invention to provide a device having improved adhesion to the skin, i.e. for which there is less likelihood that the device will become detached during use.